Abstract
Calcium activated chloride channel A4 (CLCA4), a tumor suppressor, was shown to contribute to the progression of several human cancers, while its role in bladder carcinoma remains unclear. In this study, we showed CLCA4 expression was down-regulated in bladder carcinoma tissues and cells compared to adjacent non-tumor tissues and normal urothelial cells. Low CLCA4 expression was correlated with larger tumor size, advanced tumor stage, and poor prognosis in bladder carcinoma patients. Overexpression of CLCA4 profoundly attenuated the proliferation, growth, migratory and invasive capabilities of bladder cancer cells, whereas CLCA4 knockdown had the opposite effect. Mechanistically, CLCA4 is involved in PI3K/AKT signaling and its downstream molecules can promote bladder cancer cell proliferation. Additionally, CLCA4 could mediate the migration and invasion of bladder cancer cells by regulating epithelial-mesenchymal transition and PI3K/Akt activation. This study suggests that CLCA4 may represent a promising prognostic biomarker for bladder cancer and provides a possible mechanism for bladder cancer growth and invasion.
Highlights
Bladder cancer represents the most common cancer of the urinary tract
Both western blot (WB) and realtime PCR analyses showed that chloride channel A4 (CLCA4) was profoundly down-regulated in all 7 bladder cancer cell lines compared with normal bladder urothelial cells (NBUCs) and normal urothelial cells (Figure 1C)
To further explore the molecular mechanisms of proliferation, migration and metastasis inhibited by CLCA4 in bladder cancer, Gene Set Enrichment Analysis (GSEA) of publicly available gene expression array data was analysed, and we found that CLCA4 expression was negatively associated with the activation of the PI3K/AKT and ERK signaling, and the expression of epithelial-mesenchymal transition (EMT) related genes (Figure 6A)
Summary
Bladder cancer represents the most common cancer of the urinary tract. The annual incidence rate is 80.5/100,000 in China, with an estimated mortality rate of 32.9/100,000 [1]. The clinical treatment outcomes for bladder cancer have improved in recent decades, the survival time of patients with invasive stage tumors or metastatic diseases remains very short. The median survival time of these patients is about 14 months, while the long-term disease-free survival rate is only 15% [2]. Tumor progression and migration are the most ruinous aspects of bladder cancer and directly impact the clinical survival of patients, the underlying mechanisms of these processes remain elusive. It is necessary to investigate the underlying mechanisms of bladder cancer development and identify effective therapeutic strategies to improve patient survival
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